The five dimensions of B cell tolerance

Abstract

B cell tolerance has been generally understood to be an acquired property of the immune system that governs antibody specificity in ways that avoid auto-toxicity.As useful as this understanding has proved, it fails to fully explain the existence of auto-reactive specificities in healthy individuals and contribution these may have to health. Mechanisms underlying B cell tolerance are considered to select a clonal repertoire that generates a collection of antibodies that do not bind self, ie tolerance operates more or less in three dimensions that largely spare autologous cells andantigens. Yet, most B lymphocytes in humans and probably in other vertebrates are auto-reactive and absence of these auto-reactive B cells is associated with disease.We suggest that auto-reactivity can be embodied by extending the concept of tolerance by two further dimensions, one of time and circumstance and one that allows healthy cells to actively resist injury. In this novel concept, macromolecular recognition by the B cell receptor leading to deletion, anergy, receptor editing or B cell activation is extended by taking account of the time of development of normal immune responses (4th dimension) and the accommodation (or tolerance) of normal cells to bound antibody, activation of complement, and interaction with inflammatory cells (fifth dimension). We discuss how these dimensions contribute to understanding B cell biology in health or disease. K E Y W O R D S

HLA-G: An Important Mediator of Maternal-Fetal Immune-Tolerance

“…T and B cells are the basis of immunological tolerance (54)(55)(56). To tolerize self-antigens, T and B cells first experience central tolerance and subsequently form peripheral tolerance.…”

Development of a Novel Circulating Autoantibody Biomarker Panel for the Identification of Patients with ‘Actionable’ Pulmonary Nodules

“…Our efforts to identify markers that held value for discerning patients with actionable versus non-actionable nodules were focused on the discovery of circulating autoantibodies. To avoid autotoxicity, B-cells generally have a central and peripheral tolerance, which prevents them from producing autoantibodies targeted at self-antigen [ 28 ]. However, it is believed that B-cells can overcome their peripheral tolerance when tumors produce autoantigens that are overly expressed, expressed in areas of the body they typically are not, or are a result of a mutation that leads to an antigenic (or neoantigenic) protein [ 29 ].…”

TNFRSF13B in B cell responses to organ transplantation

“…TNFRSF13B function might also benefit organ xenografts by enabling development of accommodation. Accommodation refers to acquired resistance to immune and inflammatory injury and much of the original work on accommodation reflected observations that over time organ xenografts can acquire resistance to antibody-mediated injury and rejection [ 73 , 75 , 76 ]. We think TNFRSF13B functions, including the slowing T cell-dependent B cell responses, providing of a broad range of antibody avidities, providing natural antibodies that divert complement from cell surfaces and facilitate repair among other functions listed above shift help antibody-induced accommodation to eclipse antibody-mediated injury and rejection.…”

“…Antibody responses in these settings occur in bursts and T cell dependent responses exhibit higher average avidity, owing to impact on selection and possibly somatic hypermutation. Although the concentration of antigen specific antibodies is not higher and may be lower than concentrations detected in wild type individuals, the rapid increase and high avidity make the antibodies more effective in host defense and more pathogenic in transplantation and possibly autoimmunity (see [ 20 , 69 , 73 ] for review). Conceivably, one might use a drug or biological agent to act on the receptor to slow production and lower average avidity of antibodies produced in T cell-dependent B cell responses.…”